Project Summary/Abstract Human immunodeficiency virus-1 (HIV) enters the central nervous system (CNS) early after primary infection and results in a spectrum of cognitive deficits, collectively termed HIV associated neurocognitive disorders (HAND). While successful in reducing peripheral viral loads to undetectable levels, antiretroviral therapy (ART) does not effectively quell CNS viremia to the same extent. As a result, ART has not decreased the prevalence of HAND, which continues to increase as the life expectancy for seropositive individuals rises. HIV-infected substance abusers exhibit more severe cognitive impairment compared with their non-drug abusing counterparts. Specifically, cocaine use is associated with an accelerated incidence and progression of HAND. This occurs, in part, due to cocaine-mediated increases in HIV replication and resultant blood-brain barrier perturbations, neuroinflammatory responses, and neuronal damage that contribute to the sequelae characteristic of HAND. To understand more fully the impact of cocaine use on the pathogenesis of HAND, I will examine three major mechanisms by which cocaine may interfere with ART effectiveness in the CNS. In Aim 1, I will evaluate the impact of cocaine on ART metabolism by HIV infected macrophages/microglia. These analyses will occur during the K99 phase. Aim 2 will also be performed during the K99 phase, where I will determine the distribution of ART in the brain during comorbid HIV infection and cocaine use by mass spectrometric imaging. In the R00 phase of the award, I will characterize the association between polymorphisms in drug metabolizing enzymes and HAND during Aim 3. Finally, Aim 4 will be performed in the remainder of the R00 phase where I will evaluate the transport of ART across the BBB in the context of cocaine. My past experience with the blood-brain barrier, HAND, and substance abuse will be combined with my current training in CNS-specific innate immune responses and the molecular biology of HIV pathogenesis. However, I require additional training in pharmacology of ART, mass spectrometric modalities, and pharmacogenetics. The institutional resources and outstanding mentorship available at the Johns Hopkins University provide a supportive and rich training environment in which to develop an independent research program. In the K99 phase, I will receive mentorship from a team of distinguished leaders in their respective fields: Drs. Clements, Bumpus, McArthur, and Haughey. Under their guidance and with their support, I will receive technical training in experimental concepts and development of appropriate methodologies, which will be complimented by networking opportunities at national and international scientific meetings. Successful completion of the mentorship, didactic training, research, and career development activities afforded by this K99/R00 Pathway to Independence Award will provide the strong foundation necessary for my successful transition to an independent investigator.